Therapeutic modulation of APP-CD74 axis can activate phagocytosis of TAMs in GBM

Glioblastoma multiforme (GBM) remains the most lethal central nervous system cancer with poor survival and few targeted therapies. The GBM tumor microenvironment is complex and closely associated with outcomes. Here, we analyzed the cell-cell communication within the microenvironment and found the high level of cell communication between GBM tumor cells and tumor-associated macrophages (TAMs). We found that the amyloid protein precursor (APP)-CD74 axis displayed the highest levels of communication between GBM tumor cells and TAMs, and that APP and CD74 expression levels were significantly corelated with poorer patient outcomes. We showed that the expression of APP on the surface of GBM inhibited phagocytosis of TAMs through the binding of APP to the CD74/CXCR4 cell surface receptor complex. We further demonstrated that disrupting the APP-CD74 axis could upregulated the phagocytosis of TAMs in vitro and in vivo. Finally, we demonstrated that APP promotes the phosphorylation of SHP-1 by binding to CD74. Together, our findings revealed that the APP-CD74 axis was a highly expressed anti-phagocytic signaling pathway that may be a potential immunotherapeutic target for GBM. •The interaction between APP and CD74 played a key role in tumor microenvironment of GBM.•APP on GBM cells binds to CD74 on TAMs, delivering an inhibitory signal that suppresses the phagocytic activity of TAMs.•Blocking the APP-CD74 enhances the innate immune response against GBM, representing a potential new therapeutic strategy.